Background-Specific transcription factors (TFs) modulate cardiac gene expression in murine models of heart failure, but their relevance in human subjects remains untested. We developed and applied a computational approach called transcriptional genomics to test the hypothesis that a discrete set of cardiac TFs is associated with human heart failure. Methods and Results-RNA isolates from failing (nϭ196) and nonfailing (nϭ16) human hearts were hybridized with Affymetrix HU133A arrays, and differentially expressed heart failure genes were determined. TF binding sites overrepresented in the Ϫ5-kb promoter sequences of these heart failure genes were then determined with the use of public genome sequence databases. Binding sites for TFs identified in murine heart failure models (MEF2, NKX, NF-AT, and GATA) were significantly overrepresented in promoters of human heart failure genes (PϽ0.002; false discovery rate 2% to 4%). In addition, binding sites for FOX TFs showed substantial overrepresentation in both advanced human and early murine heart failure (PϽ0.002 and false discovery rate Ͻ4% for each). A role for FOX TFs was supported further by expression of FOXC1, C2, P1, P4, and O1A in failing human cardiac myocytes at levels similar to established hypertrophic TFs and by abundant FOXP1 protein in failing human cardiac myocyte nuclei. Conclusions-Our results provide the first evidence that specific TFs identified in murine models (MEF2, NKX, NFAT, and GATA) are associated with human heart failure. Moreover, these data implicate specific members of the FOX family of TFs (FOXC1, C2, P1, P4, and O1A) not previously suggested in heart failure pathogenesis. These findings provide a crucial link between animal models and human disease and suggest a specific role for FOX signaling in modulating the hypertrophic response of the heart to stress in humans.

PURPOSE The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.

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Background-Heart failure results from abnormalities in multiple biological processes that contribute to cardiac dysfunction. We tested the hypothesis that inherited variation in genes of known importance to cardiovascular biology would thus contribute to heart failure risk. Methods and Results-We used the ITMAT/Broad/CARe cardiovascular single-nucleotide polymorphism array to screen referral populations of patients with advanced heart failure for variants in Ϸ2000 genes of predicted importance to cardiovascular biology. Our design was a 2-stage case-control study. In stage 1, genotypes in Caucasian patients with heart failure (nϭ1590; ejection fraction, 32Ϯ16%) were compared with those in unaffected controls (nϭ577; ejection fraction, 67Ϯ8%) who were recruited from the same referral centers. Associations were tested for independent replication in stage 2 (308 cases and 2314 controls). Two intronic single-nucleotide polymorphisms showed replicated associations with all-cause heart failure as follows: rs1739843 in HSPB7 (combined Pϭ3.09ϫ10